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Presentation Is Essential for Glycan-Lectin Recognition at the Molecular and Cellular Levels

2025-12-29Artigo científico Acesso aberto
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dc.contributor.authorGrosso, Ana Sofia
dc.contributor.authorDiniz, Ana
dc.contributor.authorSoares, Cátia O.
dc.contributor.authorGoerdeler, Felix
dc.contributor.authorGimeno, Ana
dc.contributor.authorCoelho, Pedro
dc.contributor.authorCoelho, Helena
dc.contributor.authorLima, Carlos D.L.
dc.contributor.authorPinheiro, Benedita
dc.contributor.authorLete, Marta G.
dc.contributor.authorGarcia-Martin, Fayna
dc.contributor.authorJaroentomeechai, Thapakorn
dc.contributor.authorGomes, Joana
dc.contributor.authorReis, Celso A.
dc.contributor.authorWesterlind, Ulrika
dc.contributor.authorCorzana, Francisco
dc.contributor.authorPalma, Angelina S.
dc.contributor.authorClausen, Henrik
dc.contributor.authorJiménez-Barbero, Jesús
dc.contributor.authorvan Vliet, Sandra J.
dc.contributor.authorNarimatsu, Yoshiki
dc.contributor.authorMarcelo, Filipa
dc.contributor.institutionUCIBIO - Applied Molecular Biosciences Unit
dc.contributor.institutionDQ - Departamento de Química
dc.contributor.pblACS - American Chemical Society
dc.date.accessioned2026-03-23T11:03:02Z
dc.date.available2026-03-23T11:03:02Z
dc.date.issued2025-12-29
dc.descriptionPublisher Copyright: © 2025 The Authors. Published by American Chemical Society
dc.description.abstractThe human macrophage galactose-type lectin (MGL) recognizes exposed GalNAc residues abundantly found in tumor O-glycans. Herein, we have used an integrative chemical, structural, and functional approach to unravel the intricate specificity and molecular determinants that underlie the recognition of Thomsen-nouveau (Tn), the sialylated variant (STn), and Thomsen-Friedenreich (TF) O-glycans by the carbohydrate recognition domain of the MGL (MGL-CRD) at the molecular and cellular levels. The MGL-CRD prefers binding to Tn > STn ≫ TF O-glycans. In this molecular context, NMR, isothermal titration calorimetry, and molecular dynamics simulations revealed quantitative key structural and dynamic differences in binding, depending on the O-glycan. Interestingly, the density of Tn epitopes was critical for engaging multiple MGL-CRDs to MUC1 Tn-glycopeptides; however, the enthalpy–entropy balance strongly influenced the affinity, and a higher Tn density did not improve the binding. Cell-based mucin arrays recapitulated the MGL-CRD binding preference (Tn > STn ≫TF), but no preference for a specific O-glycan pattern in mucins was observed. The MGL-CRD also selectively recognizes glycoengineered gastric cancer cells expressing Tn/STn. Conversely, in the cellular context, employing CHO cells expressing the full-length MGL (CHO+MGL) allowed analysis of the MGL binding properties in its native presentation toward tagged isolated mucin reporters. Specificity for short tumor-associated O-glycans without any preference for a specific mucin was confirmed. Stunningly, the CHO+MGL cells revealed that the MGL shows similar binding to the STn and TF mucin reporters, suggesting that its natural oligomeric state displays promiscuous binding to simple O-glycans. Conceptually, the key role of glycan and lectin presentations for binding is thus highlighted. Moreover, this suggests the compelling scenario that the MGL serves as a universal receptor for truncated cancer-associated O-glycans.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent13
dc.format.extent8825096
dc.identifier.doi10.1021/jacsau.5c00905
dc.identifier.issn2691-3704
dc.identifier.otherPURE: 158207876
dc.identifier.otherPURE UUID: d6fc55ff-5310-48ff-b40b-51327e3686f5
dc.identifier.otherScopus: 105028306402
dc.identifier.otherORCID: /0000-0001-5797-6555/work/209454296
dc.identifier.otherORCID: /0000-0001-5049-8511/work/209454532
dc.identifier.otherWOS: 001650824600001
dc.identifier.otherPubMed: 41614153
dc.identifier.otherPubMedCentral: PMC12848722
dc.identifier.urihttp://hdl.handle.net/10362/201731
dc.identifier.urlhttps://www.scopus.com/pages/publications/105028306402
dc.identifier.urlhttps://www.webofscience.com/wos/woscc/full-record/WOS:001650824600001
dc.language.isoeng
dc.peerreviewedyes
dc.subjectGlycan and receptor presentation
dc.subjectMacrophage galactose-type lectin
dc.subjectMolecular recognition
dc.subjectTumor-associatedO-glycans
dc.subjectAnalytical Chemistry
dc.subjectChemistry (miscellaneous)
dc.subjectPhysical and Theoretical Chemistry
dc.subjectOrganic Chemistry
dc.subjectSDG 3 - Good Health and Well-being
dc.titlePresentation Is Essential for Glycan-Lectin Recognition at the Molecular and Cellular Levelsen
dc.title.subtitleThe Interaction of Tumor-Associated O-Glycans with the Macrophage Galactose-Type Lectinen
dc.typejournal article
degois.publication.firstPage82
degois.publication.issue1
degois.publication.lastPage94
degois.publication.titleJACS Au
degois.publication.volume6
dspace.entity.typePublication
rcaap.rightsopenAccess

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